The cellular mechanisms responsible for ethanol intoxication, reinforcement, and dependence are not fully understood. There is now considerable evidence that ethanol modulates several neurotransmitter systems in the brain to shift the balance between excitatory and inhibitory synaptic transmission in favor of inhibition. For example, a large number of behavioral, neurochemical and electrophysiological studies have shown that ethanol acts, at least in part, by enhancing synaptic inhibition mediated by GABAA receptors. Despite the large volume of evidence linking GABAA receptors and ethanol, the specific mechanism(s) through which ethanol enhances GABAA receptor-mediated synaptic transmission are not clearly understood nor are the factor(s) responsible for regulating the ethanol sensitivity of GABAergic synapses. Based on preliminary studies, we propose that the ethanol sensitivity of GABAergic synapses in the rat hippocampus is regulated by a previously unrecognized presynaptic effect of ethanol on metabotropic GABAB receptors at these synapses. By potentiating GABAB autoreceptor function, ethanol enhances feedback inhibition of GABA release and this mechanism serves to limit the overall potentiating effect of ethanol at these synapses. We hypothesize that this novel presynaptic effect of ethanol contributes to the differential sensitivity of GABAergic synapses that has been noted within and between brain regions. We further propose that differences in presynaptic GABAB receptor function may contribute to differences in the ethanol sensitivity of GABAergic synapses that have been observed between lines of animals bred for differences in behavioral sensitivity to ethanol. The results of these studies will shed new light on a novel presynaptic mechanism that regulates the ethanol sensitivity of GABAergic synapses in the rat hippocampus and determine the extent to which this mechanism contributes to the differential ethanol sensitivity of some GABAergic synapses. Since studies suggest a link between initial ethanol sensitivity and subsequent risk of alcoholism, these studies may reveal novel synaptic gene products that may be associated with alcoholism and may possibly provide new targets for the development of pharmacotherapies to treat this disease.